Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-01-24
1997-11-25
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544328, 544331, C07D47102, C07D40914, C07D31196, A61K 3135
Patent
active
056913443
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based upon PCT Application Ser. No. PCT/EP 94/02700, filed Aug. 12, 1994, which claims priority from European Patent Application Serial No. 93.202.440.9, filed on Aug. 19, 1993.
The present invention relates to novel substituted dihydropyranopyridines, processes for their preparations, pharmaceutical compositions containing them and their use as a medicine, in particular for the prevention or treatment of disorders characterized by excessive vasodilatation, especially migraine.
Migraine is a non-lethal disease suffered by one in ten individuals. The main symptom is headache; other symptoms include vomiting and photophobia. For many years the most widely used treatment for migraine involved the administration of ergotalkaloids, which show however several adverse side effects. Recently a tryptamine derivative, i.e. sumatriptan, was introduced as a novel antimigraine drug. We have now surprisingly found that the present novel substituted dihydropyranopyridines show 5-HT.sub.1 -like agonistic activity and can thus be used in the treatment of disorders characterized by excessive vasodilatation, especially migraine.
The present invention is concerned with compounds of formula ##STR3## the pharmaceutically acceptable acid addition salts thereof, the N-oxides thereof and the stereochemically isomeric forms thereof, wherein .dbd.a.sub.1 --a.sub.2 .dbd.a.sub.3 --a.sub.4 .dbd. is a bivalent radical of formula: substituted by halo, hydroxy, C.sub.1-6 alkyl or C.sub.1-6 alkyloxy;
R.sup.1 is hydrogen or C.sub.1-6 alkyl;
R.sup.2 is hydrogen or C.sub.1-6 alkyl;
R.sup.3 is hydrogen or C.sub.1-6 alkyl;
Alk.sup.1 is C.sub.1-5 alkanediyl;
Alk.sup.2 is C.sub.2-15 alkanediyl;
Q is a radical of formula ##STR4## wherein
R.sup.4 is hydrogen, cyano, aminocarbonyl or C.sub.1-6 alkyl;
R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 alkenyl or C.sub.3-6 alkynyl;
R.sup.6 is hydrogen or C.sub.1-6 alkyl; or
R.sup.5 and R.sup.6 taken together may form a bivalent radical of formula --(CH.sub.2).sub.4 -- or --(CH.sub.2).sub.5 --;
R.sup.7 and R.sup.8 each independently are hydrogen, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, mono- or di(C.sub.3-6 cycloalkyl)amino, aminocarbonyl, C.sub.1-6 alkyloxycarbonylamino, C.sub.1-6 alkylaminocarbonylamino, piperidinyl, pyrrolidinyl;
R.sup.9 is hydrogen, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, mono- or di(C.sub.3-6 cycloalkyl)amino, aminocarbonyl, C.sub.1-6 alkyloxycarbonylamino, C.sub.1-6 alkylaminocarbonylamino, piperidinyl, pyrrolidinyl;
R.sup.10 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, or aryl C.sub.1-6 alkyl;
R.sup.11 and R.sup.12 are hydrogen or taken together with the carbon atom to which they are connected form C(O);
q is 1 or 2;
R.sup.13 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, or arylC.sub.1-6 alkyl;
R.sup.14 is hydrogen, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, mono- or di(C.sub.3-6 cycloalkyl)amino, aminocarbonyl, C.sub.1-6 alkyloxycarbonylamino, C.sub.1-6 alkylaminocarbonylamino, piperidinyl, pyrrolidinyl;
R.sup.15 and R.sup.16 each independently are hydrogen, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, mono- or di(C.sub.3-6 cycloalkyl)amino, aminocarbonyl, C.sub.1-6 alkyloxycarbonylamino, C.sub.1-6 alkylaminocarbonylamino, piperidinyl, pyrrolidinyl;
R.sup.17 and R.sup.18 each independently are hydrogen, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, mono- or di(C.sub.3-6 cycloalkyl)amino, aminocarbonyl, C.sub.1-6 alkyloxycarbonylamino, C.sub.1-6 alkylaminocarbonylamino, piperidinyl, pyrrolidinyl;
R.sup.19 and R.sup.20 each independently are hydrogen, hydroxy, halo, C.sub
REFERENCES:
patent: 5071871 (1991-12-01), Blarer et al.
patent: 5137901 (1992-08-01), Junge et al.
patent: 5140031 (1992-08-01), Atwal et al.
patent: 5250540 (1993-10-01), Arlt et al.
Andrés-Gil José Ignacio
Fernandez-Gadea Francisco Javier
Matesanz-Ballesteros Maria Encarnacion
Van Lommen Guy Rosalia Eugene
Janssen Pharmaceutica N.V.
Metz Charles J.
Ngo Tamthom T.
Shah Mukund J.
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